Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats
Abstract
Background & aims Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC).Methods Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis.Results Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver.Conclusions The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development.
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High circulating lipopolysaccharide levels in mice and patients with chronic liver disease and hepatocellular carcinoma demonstrate a leaky gut during multiple stages of chronic liver disease and hepatocarcinogenesis.
“High circulating LPS levels in mice and patients with CLD as well as in HCC14,24,77,78 demonstrate the presence of a leaky gut during multiple stages of CLD and hepatocarcinogenesis (FIG. 1).”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [77]
Perturbation of gut eubiosis by penicillin increased hepatocellular carcinoma formation in rats, and this increase could be suppressed by probiotics.
“As such, perturbation of the gut eubiosis by penicillin increased HCC formation in rats77, which could be suppressed by probiotics77.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [77]
In a rat model of DEN-induced hepatocarcinogenesis, VSL#3 mitigated enteric dysbiosis, reduced intestinal inflammation, and decreased liver tumour growth and multiplicity.
“In a rat model of DEN-induced hepatocarcinogenesis, administration of VSL#3 (containing Streptococcus thermophiles, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus) mitigated enteric dysbiosis, ameliorated intestinal inflammation and decreased liver tum”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [77]
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- Authors
- Zhang, H.-L., Yu, L.-X., Yang, W., Tang, L., Lin, Y., Wu, H., Zhai, B., Tan, Y.-X., Shan, L., Liu, Q., Chen, H.-Y., Dai, R.-Y., Qiu, B.-J., He, Y.-Q., Wang, C., Zheng, L.-Y., Li, Y.-Q., Wu, F.-Q., Li, Z., Yan, H.-X., & Wang, H.-Y.
- Affiliations
- Second Military Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Yan, He-Xin
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 57
- Issue
- 4
- Pages
- 803-812
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2041989558
- Cited by
- 281
- References
- 36
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 33 · 2023: 21 · 2022: 35 · 2021: 39 · 2020: 28 · 2019: 28 · 2018: 23 · 2017: 18 · 2016: 7 · 2015: 10 · 2014: 5 · 2013: 8 · 2012: 1
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- intestinal homeostasis, gut microbiota, hepatocellular carcinoma, hepatocarcinogenesis, probiotics, diethylnitrosamine, dextran sulfate, gut dysbiosis, intestinal inflammation, endotoxin translocation, HMGB1, damage-associated molecular patterns, pathogen-associated molecular patterns, Lactobacillus, Bifidobacterium, Enterococcus, liver cirrhosis, cytokines
- MeSH terms
- Alkylating Agents, Animals, Anti-Bacterial Agents, Bifidobacterium, Diethylnitrosamine, Endotoxins, Gastroenteritis, Carcinoma, Hepatocellular, Homeostasis, Humans, Lactobacillus, Liver Cirrhosis, Liver Neoplasms, Experimental, Male, Penicillins, Cytokines, Dextran Sulfate, Enterococcus, Rats, Sprague-Dawley, Disease Progression, Probiotics, HMGB1 Protein, Gastrointestinal Tract, Rats
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